A Theory of Localized Iron Accumulation Facilitating Chronic and Concurrent Neurodegeneration

Iron is essential in all cells, but paradoxically accumulates in various regions across neurodegenerative diseases including Multiple Sclerosis, Alzheimer’s disease, traumatic brain injuries, frontotemporal dementia, Amyotrophic Lateral Sclerosis, stroke, and Lewy bodies associated with Parkinson’s. Furthermore, neurodegenerative pathologies frequently co-exist or compound; when such pathologies threshold into clinical progression across (overlapping) neurodegenerative diseases remain unexplained. We propose a new unifying theory: localized iron accumulation facilitates chronic neurodegeneration, wherein location-specific and temporal iron accumulation result in individual and concurrent neurodegenerative diseases. Excess ferrous iron can trigger ferroptosis, while ferric iron stored in ferritin involves cellular senescence: complementary and self-sustaining processes promoting oxidative stress, mitochondrial and endolysosomal dysfunction, and other hallmarks involved in chronic neurodegeneration. Finally, our proposed ferroptotic-senescence axis novelly accounts for both singular and compound proteinopathies. Our theory highlights important, novel priorities for diagnostics to screen for concurrent neurodegenerative diseases, and therapeutics for targeting iron-driven cell death and senescence.